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The dual inhibition of RNA Pol I transcription and PIM kinase as a new therapeutic approach to treat advanced prostate cancer.

Research paper by Richard J RJ Rebello, Eric E Kusnadi, Donald P DP Cameron, Helen B HB Pearson, Analia A Lesmana, Jennifer R JR Devlin, Denis D Drygin, Ashlee K AK Clark, Laura L Porter, John J Pedersen, Shahneen S Sandhu, Gail P GP Risbridger, Richard B RB Pearson, Ross D RD Hannan, Luc L Furic

Indexed on: 04 Aug '16Published on: 04 Aug '16Published in: Clinical cancer research : an official journal of the American Association for Cancer Research



Abstract

The MYC oncogene is frequently over-expressed in prostate cancer (PC). Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. Additionally, PIM kinases activate MYC signaling and mRNA translation in PC and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat PC.The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription has been successfully exploited therapeutically, but only in models of hematological malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in PC cell lines, in Hi-MYC and PTEN-deficient mouse models and in patient derived xenografts (PDX) of metastatic tissue obtained from a castration-resistant PC patient.CX-5461 inhibited anchorage-independent growth and induced cell cycle arrest in PC cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced p53 expression and activity and reduced proliferation (Ki-67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of PC.Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of PC.

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